Approximately 5.7 million women in the US meet criteria alcohol use disorder (AUD). While this figure remains significantly lower than men, the traditional gender gap is rapidly converging as a result of sharp elevations in women drinking patterns due, in part, to socioeconomic gains within the labor force. As gender- specific risk factors for AUD place women at a considerable disadvantage in terms of clinical health outcomes, this sharp increase in alcohol consumption urgently necessitates the development of interventions that have been specifically tailored to women. In view of this, preliminary data from our laboratory has shown that the alpha2 adrenergic agonist, guanfacine, attenuates the negative reinforcing effects of alcohol and enhances cognitive regulation in the face of stress, preferentially in early abstinent women compared with men. We suggest that this may be due to gender-specific variation in sympathetic sensitivity. Thus, we propose a double blind, placebo-controlled, 10-week randomized clinical trial to examine the preliminary effects of guanfacine extended release (GXR, 3mgs/daily) in 60 women with AUD. A parallel 2-day experimental study using a stress versus neutral imagery exposure paradigm will also be conducted following 4 weeks of treatment (when at full dose), to examine the stress-related subjective and biological markers of change underpinning guanfacine's efficacy. Sixty women with AUD will be recruited to take part in the 10-week outpatient trial for GXR (3mgs/daily) versus placebo (PLA). This will include twice weekly appointments comprising medical management and contingency management protocols, collection of urine, breathalyzer screens, and vitals. Measures of craving and mood will also be assessed. Participants who maintain abstinence for 4 weeks will take part in 2 laboratory challenge sessions, where they will be exposed to a personal stress versus relaxing imagery condition, 1 condition per day, in a randomized order. Craving, anxiety, mood, cognitive control, HRBP, and biological stress system markers will be assessed at baseline, following imagery and at various recovery time- points. A follow-up interview will be conducted 30 days following outpatient completion. In view of prior research, we anticipate that GXR will be safe and well tolerated in women with AUD (H1); lead to greater abstinence and treatment adherence compared with the PLA group (primary outcome measures) (H2a) as well as greater attenuation of withdrawal symptoms and improved regulatory function (secondary outcome measures) both during outpatient treatment (H2b) and following stress exposure in the laboratory (H3a). We also anticipate that GXR-related changes to stress response in the laboratory will predict improved primary alcohol use outcomes (H3b). Findings will help to elucidate unique stress-system mechanisms which support attenuation of drinking in women with AUD prior to further assessment in larger randomized clinical trials. This is of paramount importance to developing medications that are integral to the health and well-being of an increasingly vulnerable sub-population of drinkers.